Substituted azabicycloheptanes, the use thereof, pharmaceutical preparations that contain these compounds, and processes for the manufacture of these compounds

ABSTRACT

1-phenyl-3-azabicyclo[3.1.1]-heptane-2,4-diones of the formula ##STR1## in which R 1  represents hydrogen or a saturated or unsaturated, aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic or aromatic-aliphatic hydrocarbon radical having up to and including 18, preferably up to and including 12, carbon atoms, R 2  represents hydrogen, lower alkyl, sulpho or acyl, R 3  represents hydrogen or lower alkyl and R 4  represents hydrogen, lower alkyl, phenyl or phenyl substituted by --N(R 2 )(R 3 ), and salts of these compounds, have valuable pharmacological properties, are effective as aromatase inhibitors and can therefore be used for the treatment of hormone-dependent diseases, especially mammary carcinoma.

This is a divisional of application Ser. No. 746,814 filed on June 20,1985 now U.S. Pat. No. 4,677,129.

The present invention relates to novel aminophenyl-substitutedazabicycloalkanes having valuable pharmacological properties and tosalts of these compounds, to the use of these substances andpharmaceutical preparations that contain these substances, topharmaceutical preparations and to processes for the manufacture ofthese novel substances, and also to intermediates and processes for themanufacture of these intermediates.

The present invention relates to substituted1-phenyl-3-azabicyclo[3.1.1]heptane-2,4-diones of the formula ##STR2##in which R₁ represents hydrogen or a saturated or unsaturated,aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic oraromatic-aliphatic hydrocarbon radical having up to and including 18,preferably up to and including 12, carbon atoms, R₂ represents hydrogen,lower alkyl, sulpho or acyl, R₃ represents hydrogen or lower alkyl andR₄ represents hydrogen, lower alkyl, phenyl or phenyl substituted by--N(R₂)(R₃), and to salts of these compounds.

In the description of the present invention, the term "lower" used inthe definition of groups or radicals, for example lower alkyl, loweralkoxy, lower alkanoyl, etc., denotes that the groups or radicals sodefined, unless expressly defined otherwise, contain up to and including7, and preferably up to and including 4, carbon atoms.

The general terms and definitions used in the description preferablyhave the following meanings:

The group --N(R₂)(R₃) may be in the 2-, 3- or 4-position of the phenylradical.

A saturated or unsaturated, aliphatic, cycloaliphatic orcycloaliphatic-aliphatic hydrocarbon fradical R₁ is, for example, alkyl,alkenyl, lower alkynyl, cycloalkyl, cycloalkenyl, cycloalkyl-loweralkyl, cycloalkyl-lower alkenyl, cycloalkenyl-lower alkyl orunsubstituted or substituted aryl or aryl-lower alkyl.

Alkyl R₁ has, for example, from 1 to 12 carbon atoms and is, forexample, lower alkyl having from 1 to 7 carbon atoms, for examplemethyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert.-butyl,n-pentyl, neopentyl, n-hexyl or n-heptyl, and n-octyl, n-nonyl, n-decyl,n-undecyl or n-dodecyl.

Alkenyl R₁ has, for example, from 2 to 12 carbon atoms and is, forexample, lower alkenyl having from 3 to 7 carbon atoms, for exampleallyl or 2- or 3-butenyl, and 2-octenyl, 2-nonenyl, 2-decenyl,2-undecenyl or 2-dodecenyl, it also being possible for the double bondto be in a position other than the 2-position.

Lower alkynyl R₁ has, for example, from 2 to 7, especially from 3 to 4,carbon atoms and is, for example, 2-propynyl or 2-butynyl.

Cycloalkyl R₁ contains, for example, from 3 to 10, especially from 3 to6, carbon atoms and is, for example, cyclopropyl, cyclobutyl,cyclopentyl or cyclohexyl.

Cycloalkenyl R₁ contains, for example, from 3 to 10, especially from 3to 6, carbon atoms and is, for example, 2-cyclohexenyl or2,5-cyclohexadienyl.

Cycloalkyl-lower alkyl R₁ contains, for example, from 4 to 10,especially from 4 to 7, carbon atoms and is, for example,cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl orcyclohexylmethyl, and 2-cyclopropylethyl, 2-cyclobutylethyl,2-cyclopentylethyl or 2-cyclohexylethyl.

Cycloalkyl-lower alkenyl R₁ contains, for example, from 5 to 10,especially from 4 to 9, carbon atoms and is, for example,cyclohexylvinyl or cyclohexylallyl.

Cycloalkenyl-lower alkyl R₁ contains, for example, from 4 to 10,especially from 4 to 8, carbon atoms and is, for example,1-cyclohexenylmethyl or 1,4-cyclohexadienylmethyl, and2-(1-cyclohexenyl)-ethyl or 2-(1,4-cyclohexadienyl)-ethyl.

Unsubstituted or substituted aryl R₁ has, for example, from 6 to 12carbon atoms and is, for example, phenyl or 1- or 2-naphthyl, the phenylor naphthyl being optionally substituted by lower alkyl, hydroxy, loweralkoxy, acyloxy, amino, lower alkylamino, di-lower alkylamino, acylaminoor by halo, the substituents, of which there may be several, being inthe 2-, 3- or 4- position of the phenyl ring, for example4-methylphenyl, 4-methyl-1-naphthyl, 4-hydroxyphenyl, 3- or4-methoxyphenyl, 3,4-dimethoxyphenyl, 4-acetoxyphenyl, 3-or4-dimethylaminophenyl, 4-acetaminophenyl, 3- or 4-chlorophenyl or4-bromophenyl.

Unsubstituted or substituted aryl-lower alkyl R₁ has, for example, from7 to 15 carbon atoms and is, for example, benzyl, 2-phenylethyl or 1- or2-naphthylmethyl, it being possible for the aryl radical to besubstituted by the same groups as in aryl R₁, for example4-methylbenzyl, 4-methoxybenzyl, 3,4-dimethoxybenzyl,2-(4-methoxyphenyl)-ethyl or 4-dimethylaminobenzyl.

Lower alkyl R₂ or R₃ has the meanings given under R₁ and is preferablymethyl or ethyl.

Acyl R₂ has, for example, up to 19 carbon atoms and is derived from acarboxylic acid, a semiester of carbonic acid, carbamic acid, asubstituted carbamic acid, a sulphonic acid, amidosulphonic acid or asubstituted amidosulphonic acid.

Acyl R₂ has, for example, the formula: R^(b) -- CO--, R^(a) --O--CO--,(R^(b))(R^(b))N--CO--, R^(a) --SO₂ -- or (R^(b))(R^(b))N--SO₂ -- inwhich R^(a) represents a saturated or unsaturated, aliphatic,cycloaliphatic or cycloaliphatic-aliphatic hydrocarbon radical having upto and including 18, preferably up to and including 10, carbon atoms oran aromatic or aromatic-aliphatic hydrocarbon radical having up to andincluding 18, preferably up to and including 10, carbon atoms, and R^(b)represents hydrogen or has the meanings of R^(a), it being possible iftwo radicals R^(b) are present for the two radicals R^(b) to be the sameor different.

A saturated or unsaturated, aliphatic, cycloaliphatic orcycloaliphatic-aliphatic hydrocarbon radical R^(a) or R^(b) has themeanings given under R₁ and is preferably lower alkyl, for examplemethyl or ethyl.

An aromatic or aromatic-aliphatic hydrocarbon radical R^(a) or R^(b) is,for example, phenyl, phenyl-lower alkyl, for example benzyl, ordiphenylmethyl.

Acyl R₂ is preferably lower alkanoyl, for example formyl or acetyl, orlower alkanesulphonyl, for example methane- or ethane-sulphonyl.

Lower alkyl R₄ is, for example, methyl, ethyl, n-propyl, isopropyl,n-butyl, isobutyl, tert.-butyl, n-pentyl, neopentyl, n-hexyl orn-heptyl.

In a phenyl radical R substituted by --N(R₂)(R₃), R₂ and R₃ have themeanings given above, it being possible for the phenyl ring to besubstituted in the 2-, 3- or 4-position.

Salts of compounds of the formula I according to the invention having asalt-forming group are especially pharmaceutically acceptable non-toxicsalts.

Such salts are formed, for example, by the amino group at the phenylring by the addition of an inorganic acid, for example hydrochloricacid, sulphuric acid, lower alkanesulphonic acid or phosphoric acid, andare, for example, hydrochlorides, bisulphates, methanesulphonates,hydrogen phosphates or dihydrogen phosphates.

Other acid addition salts are formed, for example, from carboxylic acidsand are, for example, formates, acetates, trifluoroacetates, benzoates,citrates, tartrates or salicylates.

The compounds of the formula I may also be in the form of hydrates.

The present invention relates especially to compounds of the formula Iin which R₁ represents hydrogen, alkyl, alkenyl, lower alkynyl,cycloalkyl, cycloalkenyl, cycloalkyl-lower alkyl, cycloalkyl-loweralkenyl, cycloalkenyl-lower alkyl or unsubstituted or substituted arylor aryl-lower alkyl, R₂ represents hydrogen, lower alkyl, sulpho, loweralkanoyl or lower alkanesulphonyl, R₃ represents hydrogen or lower alkyland R₄ represents hydrogen, lower alkyl, phenyl or phenyl substituted by--N(R₂)(R₃), and to salts thereof, especially pharmaceuticallyacceptable salts thereof.

The present invention relates more especially to compounds of theformula I in which R₁ represents hydrogen, alkyl having up to andincluding 12 carbon atoms, for example lower alkyl, for example methyl,ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert.-butyl, n-pentyl,neopentyl, n-hexyl or n-heptyl, and n-octyl, n-nonyl, n-decyl, n-undecylor n-dodecyl, lower alkenyl, for example allyl or 2-butenyl, loweralkynyl, for example 2-propynyl or 2-butynyl, cycloalkyl, for examplecyclopropyl, cyclopentyl or cyclohexyl, cycloalkyl-lower alkyl, forexample cyclopentylmethyl or cyclohexylmethyl, or unsubstituted orsubstituted aryl-lower alkyl, for example benzyl or 4-methoxybenzyl, R₂represents hydrogen, lower alkyl, for example methyl, lower alkanoyl,for example acetyl, or lower alkanesulphonyl, for examplemethanesulphonyl, R₃ represents hydrogen or lower alkyl, for examplemethyl, and R₄ represents hydrogen, lower alkyl, for example methyl,ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert.-butyl, phenyl orphenyl substituted by --N(R₂)(R₃), and to salts thereof, especiallypharmaceutically acceptable salts thereof.

The present invention relates especially to compounds of the formula Iin which R₁ represents hydrogen, lower alkyl, for example methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, tert.-butyl, n-pentyl,neopentyl, n-hexyl or n-heptyl, lower alkenyl, for example allyl, loweralkynyl, for example 2-propynyl, cycloalkyl, for example cyclohexyl,cycloalkyl-lower alkyl, for example cyclohexylmethyl, R₂ and R₃represent hydrogen and R₄ represents hydrogen, lower alkyl, for examplemethyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert.-butyl,phenyl or phenyl substituted by --N(R₂)(R₃), and to pharmaceuticallyacceptable salts thereof.

The present invention relates more especially to compounds of theformula I in which the group --N(R₂)(R₃) is in the 4-position of thephenyl radical, R₁ represents hydrogen, lower alkyl, for example methyl,ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert.-butyl, loweralkenyl, for example allyl, lower alkynyl, for example 2-propynyl,cycloalkyl-lower alkyl, for example cyclohexylmethyl, R₂ and R₃represent hydrogen and R₄ represents hydrogen or lower alkyl, forexample methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl ortert.-butyl, and to pharmaceutically acceptable salts thereof.

The invention relates very especially to compounds of the formula I inwhich the group --N(R₂)(R₃) is in the 4-position of the phenyl radical,R₁ represents hydrogen, alkyl having up to and including 12 carbonatoms, for example lower alkyl, such as methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, n-pentyl, neopentyl, n-hexyl or n-heptyl,and n-octyl, n-nonyl, n-decyl, n-undecyl or n-dodecyl, lower alkenyl,for example allyl, lower alkynyl, for example 2-propynyl, cycloalkyl,for example cyclopentyl or cyclohexyl, cycloalkylmethyl, for examplecyclopentylmethyl or cyclohexylmethyl, benzyl or benzyl substituted bylower alkyl, hydroxy, lower alkoxy or by lower alkanoyloxy, for example4-methoxybenzyl, and R₂, R₃ and R₄ represent hydrogen, and topharmaceutically acceptable salts thereof.

The present invention relates especially to the compounds mentioned inthe Examples.

The invention also relates to pharmaceutical preparations containingcompounds of the formula I in which R₁, R₂, R₃ and R₄ have the abovemeanings, and to the use of these compounds in a method for thetreatment of the human or animal body.

The novel compounds of the formula I and their pharmaceuticallyacceptable salts have valuable pharmacological properties, for example,as aromatase inhibitors. The suitability of compounds of the formula Ias aromatase inhibitors can be demonstrated in vitro using humanplacental microsomes in the "aromatase assay" according to P. E. Gravesand H. A. Salhanick, Endocrinology, Vol. 105, p. 52 (1979). In this testprocedure, the formation of water having tritium isotopes and17β-oestradiol from [1β,2β-³ H]testosterone as a result of the action ofa compound of the formula I on the formation of the hydrogenated form ofthe aromatase coenzyme, nicotinamide adenine dinucleotide phosphate(NADPH), is measured. The addition of a compound of the formula Iaccording to the invention, for example of1-(4-aminophenyl)-3-n-propyl-3-azabicyclo[3.1.1]heptane-2,4-dione,substantially reduces the enzyme activity (NADPH content), resulting ina markedly lower content of water having radioactive tritium isotopesthan in the case of measurements made without the addition of a compoundof the formula I according to the invention. Furthermore, comparisonmeasurements show that, at the same concentrations, the reduction inenzyme activity resulting from the addition of a compound of the formulaI according to the invention, for example of1-(4-aminophenyl)-3-n-propyl-3-azabicyclo[3.1.1]-heptane-2,4-dione, issubstantially greater than that resulting from the addition of otherknown aromatase inhibitors, for example aminoglutethimide.

On account of their activity as aromatase inhibitors, the compounds ofthe formula I in which R₁, R₂, R₃ and R₄ have the meanings given above,or salts thereof, can be used as medicaments, for example in the form ofpharmaceutical preparations, for the treatment of hormone-dependentdisorders, for example hormone-dependent tumours, such as tumoursdependent on the overproduction of oestrogen, especially mammarycarcinoma, and hormonal anomalies, for example gynaecomastia or prostatehyperplasia, in warm-blooded animals (humans and animals) by enteral,for example oral, or parenteral administration of therapeuticallyeffective doses.

The present invention also relates to the use of these compounds asmedicaments, especially those having a carcinostatic action, in one ofthe mentioned methods for the treatment of the human or animal body.

The daily doses of such compounds for mammals, depending on the species,and for humans, depending on age and individual condition and on themethod of administration, are from approximately 1 mg to approximately100 mg, especially from 5 mg to approximately 50 mg, per kg body weight.Within this range, the doses are generally lower for parenteraladministration, for example intramuscular or subcutaneous injection orintravenous infusion, than for enteral, that is to say oral or rectal,administration.

The compounds of the formula I and pharmaceutically acceptable salts ofsuch compounds having salt-forming properties are administered orally orrectally preferably in dosage unit forms, such as tablets, dragees orcapsules or suppositories, and parenterally especially in the form ofinjectable solutions, emulsions or suspensions or in the form ofinfusion solutions, there coming into consideration as solutionsespecially solutions of salts.

The invention also relates to pharmaceutical preparations for enteral,for example oral or rectal, administration or for parenteraladministration that contain a therapeutically effective amount of acompound of the formula I, or of a pharmaceutically acceptable salt ofsuch a compound having a salt-forming group, optionally together with apharmaceutically acceptable carrier or mixture of carriers, there beingused as carriers solid or liquid, inorganic or organic substances.Appropriate dosage unit forms, especially for peroral administration,for example dragees, tablets or capsules, preferably contain fromapproximately 50 mg to approximately 500 mg, especially fromapproximately 100 mg to approximately 400 mg, of a compound of theformula I, or of a pharmaceutically acceptable salt of such a compoundthat is capable of salt formation, together with pharmaceuticallyacceptable carriers

Suitable carriers are especially fillers, such as sugars, for examplelactose, saccharose, mannitol or sorbitol, cellulose preparations and/orcalcium phosphates, for example tricalcium phosphate or calciumbiphosphate, and also binders, such as starch pastes using, for example,corn, wheat, rice or potato starch, gelatine, tragacanth,methylcellulose and/or, if desired, disintegrators, such as theabove-mentioned starches, also carboxymethyl starch, crosslinkedpolyvinylpyrrolidone, agar, alginic acid or a salt thereof, such assodium alginate. Adjuncts are especially flow-regulating agents andlubricants, for example silica, talc, stearic acid or salts thereof,such as magnesium stearate or calcium stearate, and/or polyethyleneglycol. Dragee cores can be provided with suitable coatings which areoptionally resistant to gastric juices, there being used, inter alia,concentrated sugar solutions which may contain gum arabic, talc,polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide, orlacquer solutions in suitable organic solvents or solvent mixtures or,for the production of coatings that are resistant to gastric juices,solutions of suitable cellulose-preparations, such as acetylcellulosephthalate or hydroxypropylmethylcellulose phthalate. Dyes or pigmentscan be added to the tablets or dragee coatings, for example foridentification purposes or to indicate different doses of activeingredient.

Further pharmaceutical preparations for oral administration aredry-filled capsules consisting of gelatine and also soft, sealedcapsules consisting of gelatine and a plasticiser, such as glycerine orsorbitol. The dry-filled capsules can contain the active ingredient inthe form of a granulate, for example in admixture with fillers, such aslactose, binders, such as starches, and/or glidants, such as talc ormagnesium stearate, and optionally stabilisers. In soft capsules theactive ingredient is preferably dissolved or suspended in suitableliquids, such as fatty oils, paraffin oil or liquid polyethyleneglycols, it being possible also to add stabilisers.

As rectally administrable pharmaceutical preparations there come intoconsideration, for example, suppositories that consist of a combinationof the active ingredient with a suppository base Suitable suppositorybases are, for example, natural or synthetic triglycerides, paraffinhydrocarbons, polyethylene glycols or higher alkanols It is alsopossible to use gelatine rectal capsules that contain a combination ofthe active ingredient with a base material; as base materials there comeinto consideration, for example, liquid triglycerides, polyethyleneglycols or paraffin hydrocarbons.

Especially suitable for parenteral administration are aqueous solutionsof an active ingredient in water-soluble form, for example awater-soluble salt, and also suspensions of the active ingredient, suchas corresponding oily injection suspensions, there being used suitablelipophilic solvents or vehicles, such as fatty oils, for example sesameoil, or synthetic fatty acid esters, for example ethyl oleate, ortriglycerides, or aqueous injection suspensions that contain substancesthat increase the viscosity, for example sodium carboxymethylcellulose,sorbitol and/or dextran, and, optionally, stabilisers.

The pharmaceutical preparations of the present invention can bemanufactured in a manner known per se, for example by means ofconventional mixing, granulating, confectioning, dissolving orlyophilising processes. For example, pharmaceutical preparations fororal administration can be obtained by combining the active ingredientwith solid carriers, optionally granulating a resulting mixture andprocessing the mixture or granulate, if desired or necessary after theaddition of suitable adjuncts, to form tablets or dragee cores.

The present invention also relates to processes for the manufacture ofcompounds of the formula I and salts thereof. These can be manufacturedaccording to methods known per se, for example as follows

(a) in a compound of the formula ##STR3## in which R₁ and R₄ have themeanings given under formula I and X is a group that can be convertedinto the group --N(R₂)(R₃), or in a salt thereof, X is converted intothe group --N(R₂)(R₃), or

(b) a compound of the formula ##STR4## in which R₂, R₃ and R₄ have themeanings given under formula I and Y₁ and Y₂ represent leaving groups,or a salt thereof, is cyclised by reaction with a compound that yieldsthe group >N--R₁, or

(c) a compound of the formula ##STR5## in which R₁, R₂, R₃ and R₄ havethe meanings given under formula I, or a salt thereof, is cyclised, or

(d) a compound of the formula ##STR6## in which R₁, R₂, R₃ and R₄ havethe meanings given under formula I and Y₃ represents a leaving group, ora salt thereof, is cyclised with a base,

and, if desired, a compound of the formula I obtainable according to theinvention is converted into a different compound of the formula Iaccording to the definition and/or a resulting salt is converted intothe free compound or into a different salt and/or a resulting freecompound is converted into a salt and/or a resulting mixture of isomersis separated into the individual isomers.

Process (a)

In a compound of the formula II, a group X that can be converted intothe group --N(R₂)(R₃) is, for example, a nitrogen-containing reduciblegroup, for example a nitro, nitroso, hydroxyamino or azido group, areplaceable group, for example halogen, for example chlorine, bromine oriodine, or a derivatised carboxy group, for example a carbamoyl orazidocarbonyl group, or a protected amino group from which theprotecting group is removed and replaced by hydrogen.

A nitrogen-containing reducible group, for example a nitro, nitroso,hydroxyamino or azido group, is converted into the amino group by acustomary reducing agent which, if desired, is used in the presence of asuitable catalyst and/or carrier.

As a customary reducing agent there comes into consideration especially:catalytically activated hydrogen, there being used as hydrogenationcatalyst, for example, a noble metal catalyst, for example a palladium,platinum, rhodium or nickel catalyst, or a noble metal compound, forexample platinum dioxide, which, if desired, is used with a suitablecarrier, such as carbon, barium sulphate or carbonate or calciumcarbonate; a reducing tin(II) or iron(II) salt, which is used, forexample, in the form of a chloride and, in the latter case, also in theform of a sulphate; a reducing dithionite or sulphite salt, for examplesodium dithionite, sodium sulphite or sodium bisulphite; an optionallyactivated base metal, for example activated iron, tin, zinc oraluminium, which is activated optionally in the presence of thecorresponding metal salt or a neutral salt, for example calcium,magnesium, potassium or sodium chloride; and also a sulphide, forexample hydrogen sulphide; a di- or poly-sulphide, for example sodiumdisulphide or sodium polysulphide; an alkali metal sulphide or alkalimetal bisulphide, for example sodium sulphide or sodium bisulphide;ammonium sulphide or ammonium polysulphide; a reducing agent that yieldshydrogen, for example unsubstituted or substituted hydrazine, forexample hydrazine or phenylhydrazine, which is added optionally in theform of an acid addition salt, for example in the form of ahydrochloride; or molecular hydrogen which is generated by electrolyticreduction of protons at the cathode.

The reduction with catalytically activated hydrogen is carried out atnormal pressure or elevated pressure, for example up to approximately 5bar. The reduction with the mentioned reducing agents is carried out inan acidic medium, for example in an acetic acid medium, or in a neutralmedium. The reduction with iron(II) salts is carried out under basicconditions and the reducing iron(II) hydroxide precipitates. Thereductions with dithionite salts and sulphides also take place underbasic conditions.

The reduction with agents that yield hydrogen, for example hydrazines,is accelerated by the above-mentioned hydrogenation catalysts, forexample Raney nickel, palladium-on-carbon or platinum. The electrolyticreduction of the nitro groups to form the amine is carried out atcathodes consisting of metals having high overpotential, such as lead,tin, nickel, copper or zinc. The electrolysis is generally carried outin a solution of sulphuric acid or hydrochloric acid.

The above-mentioned reducing agents are added in at least an equimolaramount, preferably in excess. The addition of an excess of reducingagent is to prevent the formation of intermediates, for example nitrosoor hydroxyamino compounds.

The reduction is preferably carried out in a solvent, for example alower alkanol, for example methanol or ethanol, a lower alkoxy-loweralkanol, for example 2-methoxy- or 2-ethoxy-ethanol, a loweralkanecarboxylic acid or an ester thereof, for example acetic acid andethyl acetate, and also an ether, for example diethyl ether,tetrahydrofuran or dioxan.

To increase the solubility especially of the salt-type reducing agentsin the reaction mixture, water can be added to the reaction mixture asrequired. The reaction is customarily carried out at temperatures offrom approximately -20° to approximately 100° C., although it can alsobe carried out at lower temperatures if highly reactive activators areused.

In a compound of the formula II, a replaceable group X, for examplehalogen, for example chlorine, bromine or iodine, is converted into thegroup --N(R₂)(R₃) using a compound that yields the group --N(R₂)(R₃),for example a compound of the formula H--N(R₂)(R₃) or a metal compoundthereof, such as ammonia, an alkali metal amide, for example lithium,sodium or potassium amide, a lower alkylamine, for example methylamine,a di-lower alkylamine, for example dimethylamine, or an acid amide inwhich a hydrogen atom of the amide group has been replaced by an alkalimetal, for example lithium, for example R^(a) --CO--NR₃ Li.

The reaction of a compound of the formula II in which X representshalogen, for example chlorine, with a compound that yields the group--N(R₂)(R₃), for example with ammonia, preferably takes place in thepresence of a catalyst, for example copper(I) oxide or copper(II) oxide,copper(I) chloride or copper(II) chloride or copper sulphate. Thereaction is carried out in a concentrated aqueous ammonia solution or,preferably, in liquid ammonia, and the reaction conditions given inHouben-Weyl, Methoden der Organischen Chemie (hereinafter referred to as"Houben-Weyl"), Vol. XI/1 "Stickstoffverbindungen", pp. 63-67, areobserved, for example elevated temperature above 100° and elevatedpressure.

The reaction of a compound of the formula II in which X representshalogen, for example chlorine, is preferably carried out with an alkalimetal amide, for example lithium or potassium amide. The amide isadvantageously added in the form of a suspension.

As solvent there is preferably used benzene or toluene and the operationis carried out in an inert gas atmosphere, for example a nitrogenatmosphere. The reaction is best carried out at elevated temperature,for example at the boiling temperature of the reaction mixture,analogously to the reaction conditions described for aromatic halogencompounds in Houben-Weyl, Vol. XI/1 "Stickstoffverbindungen", on pp.74-79.

In a compound of the formula II, a derivatised carboxy group X, forexample carbamoyl or azidocarbonyl, can be converted into the aminogroup under the reaction conditions known for reactions or degradationreactions according to Hofmann (carbamoyl) or Curtius (azidocarbonyl).

The conversion according to Hofmann of the carbamoyl compound(carboxylic acid amide) of the formula II into the amino compound of theformula I using free halogen, for example bromine, is carried out underalkaline conditions.

The conversion according to Curtius of the azidocarbonyl compound of theformula II into the amino compound of the formula I is carried outthermally with decomposition of the azidocarbonyl group.

After the rearrangement, hydrolysis is carried out under acidicconditions, for example in a dilute, aqueous mineral acid, for examplein dilute sulphuric acid.

The reaction conditions for the Hofmann and Curtius degradation aredescribed in the survey by P. A. Smith, Org. Reactions 3, 363 (1946).

Protected amino groups from which the protecting group can be removedand replaced by hydrogen are described, for example, in McOmie,"Protective Groups in Organic Chemistry", Plenum Press, London and NewYork, 1973, in "The Peptides", Vol. I, Schroder and Lubke, AcademicPress, London and New York, 1965, and in Houben-Weyl, Vol 15/1, GeorgThieme Verlag, Stuttgart, 1974.

Preferred protecting groups are groups that can be removed byacidolysis, for example lower alkoxycarbonyl, for exampletert.-butoxycarbonyl (BOC) or 2-halo-lower alkoxycarbonyl, for example2-iodoethoxycarbonyl or 2,2,2-trichloroethoxycarbonyl.

It is also possible, however, to use amino-protecting groups that can beremoved by reduction or under mild conditions with a base, for exampleespecially a benzyloxycarbonyl group or a benzyloxycarbonyl group inwhich the phenyl radical is substituted by halogen atoms, nitro groupsand/or by lower alkoxy groups, for example the p-chloro-, p-nitro- orp-methoxy-benzyloxycarbonyl group.

The removal of the protecting group is carried out in the mannergenerally known; the acid hydrolysis (acidolysis) is carried out, forexample, by means of trifluoroacetic acid. The groups that can beremoved by reduction, especially those which contain benzyl radicals,are preferably removed by hydrogenolysis, for example by hydrogenationwith palladium catalysis.

Process (b)

In a compound of the formula III, each of the leaving groups Y₁ and Y₂,independently of the other, is, for example, hydroxy, halogen, forexample chlorine, bromine or iodine, lower alkoxy, silyloxy orsulphonyloxy.

Lower alkoxy Y₁ or Y₂ is, for example, methoxy, ethoxy, n-propoxy,branched lower alkoxy, for example tert.-butoxy, or substituted loweralkoxy, for example benzyloxy, 4-nitrobenzyloxy or diphenylmethoxy.

Silyloxy Y₁ or Y₂ is, for example, tri-lower alkylsilyloxy, for exampletrimethylsilyloxy.

Sulphonyloxy Y₁ or Y₂ is, for example, lower alkanesulphonyloxy, forexample methanesulphonyloxy, benzenesulphonyloxy orp-toluenesulphonyloxy.

A compound that yields the group >N--R₁ is, for example, an alkali metalamide, for example sodium amide or potassium amide, ammonia (R₁=hydrogen), a lower alkylamine, for example methylamine (R₁ =loweralkyl), a carbonic acid amide, for example urea or 1,3-dimethylurea, ora lower alkanecarboxylic acid amide, for example formamide,N-methylformamide, acetamide or N-methylacetamide.

The reaction with a compound that yields the group >N--R₁, for examplewith ammonia or with methylamine, can be carried out stepwise. Forexample it is possible to obtain first a compound of the formula III inwhich one of the leaving groups Y₁ and Y₂ has been replaced by --NH--R₁.Such a compound, for example the monoamide, can be isolated or can beconverted into a compound of the formula I in situ by removal of HY₁ orHY₂.

A compound of the formula III in which, for example, Y₁ and Y₂ representhydroxy, can first be converted into its anhydride, for examplethermally or by dehydration with a customary dehydrating agent, forexample acetic anhydride or acetyl chloride. This anhydride can beisolated or can be converted in situ by reaction with a compound thatyields the group >N--R₁, for example a compound of the formula H₂ N--R₁,such as ammonia or methylamine, into a compound in which one of theleaving groups Y₁ and Y₂ has been replaced by --NH--R₁. Such a monoamidecan subsequently be cyclised to form a compound of the formula I byremoving the elements of water.

During the cyclisation, a total of 2 mol of HY₁ or HY₂, for example HClor HBr, are freed and are bound, for example, by using an excess of theagent that yields >N--R₁, for example ammonia or methylamine.

The reaction is preferably carried out in an inert polar solvent, forexample in benzene, toluene, xylene, chlorobenzene, dichlorobenzene,methylene chloride, ether or methanol or in mixtures thereof. Thereaction temperature is between -20° and approximately +180° C., andpreferably between +100° and +180° C. If an acid halide of the formulaIII, for example the acid dichloride, is reacted with ammonia, thereaction is preferably carried out while cooling, for example at below0°.

Process (c)

The cyclisation can be effected, for example, thermally orphotochemically.

The thermal cyclisation of the acryloylacrylamides of the formula IV canbe carried out without a solvent, but it is preferable to use solutionsin high-boiling inert solvents, for example in toluene, xylene, forexample 1,3-xylene, mesitylene, chlorobenzene, dichlorobenzene, forexample 1,3-dichlorobenzene, nitrobenzene, decalin, hexachlorobttadieneor the like. The compound of the formula IV to be cyclised is dissolvedin the solvent in a concentration of from approximately 1M toapproximately 10⁻⁶ M, preferably in a concentration of from 1M to 10⁻²M, and heated in an open vessel, if desired under a protective gas, forexample nitrogen or argon, or in a closed pressure vessel attemperatures of from approximately 100° C. to approximately 250° C.,preferably from 130° C. to 180° C., for from approximately 1 toapproximately 10 hours, preferably from 2 to 5 hours. If the operationis carried out without a solvent, the acryloylacrylamide of the formulaIV is, if desired, evaporated under reduced pressure, sprayed in alow-boiling inert solvent or introduced in powder form into a reactorthat has been heated to from approximately 200° C. to approximately 500°C. and, optionally with an inert carrier gas, such as nitrogen or argon,passed through the heated reactor.

Acryloylacrylamides of the formula IV can also be cyclised to formcompounds of the formula I photochemically, especially when R₄ is otherthan hydrogen. For this purpose, the compounds of the formula IV,together with a triplet sensitiser, for example an aryl ketone, forexample benzophenone or acetophenone, are dissolved in a photochemicallyinert solvent, for example in methylene chloride, diethyl ether,n-pentane, n-hexane, cyclohexane, benzene, toluene or the like, in aconcentration of from approximately 1M to approximately 10⁻⁶ M andirradiated with ultraviolet light of a wave length of more than 300 nm,for example with a mercury high-pressure or medium-pressure lamp inPyrex® glass or with a different filter that is impervious towavelengths below 300 nm, at temperatures of from approximately -30° C.to approximately +50° C., preferably from 0° C. to 30° C., for fromapproximately 1 hour to approximately 10 hours, preferably from 2 to 5hours. Instead of using a photochemically inert solvent and an arylketone as the triplet sensitiser, it is preferable to use a di-loweralkyl ketone, for example acetone, 2-butanone or 3-pentanone, or acycloalkanone, for example cyclohexanone, as the solvent and sensitiserfor the photochemical cyclisation.

In order to suppress undesired polymerisation reactions, it ispreferable to add to the solutions of the compounds of the formula IVduring the thermal or photochemical cyclisation a substance thateliminates radicals, for example hydroquinone,2,6-di-tert.-butyl-4-methylphenol orbis-(3-tert.-butyl-4-hydroxy-5-methylphenyl)-sulphide, in aconcentration of from approximately 0.01% to approximately 5%.

Process (d)

In a compound of the formula V or VI the leaving group Y₃ is, forexample, halogen, for example chlorine, bromine or iodine, orsulphonyloxy, for example lower alkanesulphonyloxy, for examplemethanesulphonyloxy, or arylsulphonyloxy, for examplebenzenesulphonyloxy or p-toluenesulphonyloxy.

Bases suitable for cyclisation are especially non-nucleophilic bases.Examples of such bases are alkali metal salts, for example lithium,sodium or potassium salts, of sterically hindered secondary amines, forexample branched di-lower alkylamines, dicycloalkylamines, branchedlower alkylcyclohexylamines, bis-(tri-lower alkylsilyl)-amines or thelike, for example lithium diisopropylamide, lithium dicyclohexylamide,sodium or potassium bis-(trimethylsilyl)-amide or lithium2,2,6,6-tetramethylpiperidide. Other suitable bases are alkali metalhydrides, for example potassium hydride, or branched lower alkyllithiumcompounds, for example tert.-butyllithium.

As the solvent it is preferable to use an ether, for exampletetrahydrofuran or dimethoxyethane, to which hexamethylphosphoric acidtriamide is optionally added. The reaction is best carried out under aninert gas atmosphere, for example a nitrogen or argon atmosphere, attemperatures of from approximately -80° C. to approximately +30° C., forexample at approximately -30° C.

Subsequent operations

The substituents R₁, R₂, R₃ and R₄ in a compound of the formula I can beconverted within the scope of their definitions into differentsubstituents R₁, R₂, R₃ and R₄. For example, a free amino group can beconverted into an acylamino group in which R₂ represents acyl and R₃represents hydrogen or lower alkyl. These subsequent operations arecarried out in a manner known per se, for example as follows:

Acylation of the amino group at the phenyl ring:

If, in a resulting compound of the formula I, R₂ represents hydrogen, R₃represents hydrogen or lower alkyl and R₁ represents hydrogen or ahydrocarbon radical, the free amino group at the phenyl ring can besubstituted in a manner known per se by an acyl group R₂. If R₁represents hydrogen, the nitrogen atom in position 3 of the bi-cycle(imido nitrogen atom) may, if desired, be protected by one of theamino-protecting groups mentioned above under process (a) or by adifferent amino-protecting group, such as lower alkanoyl, for exampleacetyl, lower alkenoyl, for example methacryloyl, or 1-loweralkoxycarbonyl-1-alkenyl, for example 1-methoxycarbonyl-1-vinyl

This substitution can be effected, for example, by acylation with asuitable acylating agent that introduces the corresponding acyl radicalR₂.

The amino group at the phenyl ring is in free form or in reactive (thatis to say allowing acylation), protected form, for example protected bysilyl radicals.

If the amino group at the phenyl ring in a compound of the formula I issubstituted by an acyl radical R^(a) --SO₂ --, there is used asacylating agent, for example, the corresponding sulphonic acid or areactive functional derivative thereof, especially an anhydride thereof,for example a mixed anhydride. A mixed anhydride of a sulphonic acid isformed, for example, by condensation with an inorganic acid, for examplea hydrohalic acid, for example hydrochloric acid, and is, for example,the corresponding sulphonic acid halide, for example the sulphonic acidchloride or bromide.

If the amino group is substituted by an acyl group R^(b) --CO--, thereis used as acylating agent, for example, the corresponding carboxylicacid itself or a reactive functional derivative thereof.

A reactive, that is to say forming the carboxamide function, functionalderivative of a carboxylic acid is an anhydride of this carboxylic acid,preferably a mixed anhydride. A mixed anhydride is formed, for example,by condensation with a different acid, for example an inorganic acid,for example a hydrohalic acid, and is, for example, the correspondingcarboxylic acid halide, for example the carboxylic acid chloride orbromide. A reactive functional derivative of a carboxylic acid of theformula III is also formed by condensation with a lower alkyl semiesterof carbonic acid, for example the ethyl or isobutyl semiester ofcarbonic acid.

If the amino group at the phenyl ring is substituted by an acyl radicalR having the meaning R^(a) --O--CO--, (R^(b))(R^(b))N--CO-- or(R^(b))(R^(b))N--SO₂ --, there is used as acylating agent a reactivederivative of the corresponding carbonic acid semiester or of thecorresponding carbamic acid or amidosulphonic acid. Such reactivederivatives are, for example, anhydrides, for example mixed anhydrides,that are formed by condensation with inorganic acids, such as hydrohalicacids, for example hydrochloric acid, or, if a carbamic acid is used,are also internal anhydrides, for example isocyanates.

The acylation reactions are preferably carried out in the presence of asuitable acid-binding agent, for example a suitable organic base. Asuitable organic base is, for example, an amine, for example a tertiaryamine, for example tri-lower alkylamine, for example trimethylamine ortriethylamine, a cyclic tertiary amine, for example N-methylmorpholine,a bicyclic amidine, for example a diazabicycloalkene, for example1,5-diazabicyclo[4.3.0]non-5-ene or 1,8-diazabicyclo[5.4.0]undec-5-ene(DBU), or is a base of the pyridine type, for example pyridine or4-dimethylaminopyridine. A suitable acid-binding agent is also aninorganic base, for example an alkali metal hydroxide or alkaline earthmetal hydroxide, for example sodium, potassium or calcium hydroxide.

The acylation reactions are preferably carried out in an inert,preferably anhydrous, solvent or mixture of solvents, for example indimethylformamide, methylene chloride, carbon tetrachloride,chlorobenzene, acetone, tetrahydrofuran, ethyl acetate or acetonitrile,or in mixtures thereof, optionally at reduced or elevated temperature,for example in a temperature range of from approximately -40° toapproximately +100° C., preferably from approximately -10° C. toapproximately +50° C., and optionally in an inert gas atmosphere, forexample a nitrogen atmosphere.

The acylation of the free amino group at the phenyl ring can be carriedout both in the end product of the formula I and in the intermediates ofthe formulae II, III and IV according to the method described above.

Substitution of the amino group at the phenyl ring by sulpho:

If, in a resulting compound of the formula I, R₂ represents hydrogen, R₃represents hydrogen or lower alkyl and R₁ represents hydrogen or ahydrocarbon radical, the free amino group at the phenyl ring can besubstituted by sulpho in a manner known per se.

This substitution can be effected, for example, by reacting anaminophenyl compound of the formula I with a sulphur trioxide complexwith triethylamine.

In order that, in compounds of the formula I in which R₁ is hydrogen,the nitrogen atom in position 3 of the bi-cycle (imido nitrogen atom) isnot substituted by sulpho, this nitrogen may, if desired, be protectedby one of the amino-protecting groups mentioned above.

Alkylation of the amino group at the phenyl ring:

If, in a resulting compound of the formula I, R₂ and R₃ representhydrogen, the free amino group at the phenyl ring can be substituted bytwo equivalents of a suitable alkylation agent introducing a lower alkylradical, for example an alkyl halide, for example methyl bromide, toform a di-lower alkyl-substituted amino group (R₂ and R₃ =lower alkyl).Depending on the reaction conditions, for example also when less thantwo equivalents of the alkyating agent are used, mixtures of compoundswith a di-lower alkyl-substituted amino group, with a mono-loweralkyl-substituted amino group (R₂ or R₃ =lower alkyl) or with anunsubstituted amino group are formed. These mixtures can be separated ina manner known per se, for example by fractional crystallisation or bychromatographic methods.

The free amino group at the phenyl ring can also be protected by one ofthe above-mentioned customary amino-protecting groups, for example bytert.-butoxycarbonyl, and, after subsequent metallation with a suitablemetallating reagent, the amino group protected in this manner can bealkylated with a reactive alkylating compound corresponding to the loweralkyl radical R₂ or R₃. After removing the amino-protecting groups thereis obtained an amino group that is mono-substituted by lower alkyl (R₂=H and R₃ =lower alkyl or R₂ =lower alkyl and R₃ =H).

Examples of suitable metallating reagents are lithium diisopropylamideand butyllithium. A reactive compound corresponding to the radical R₃is, for example, a compound of the formula R₂ --X or R₃ --X in which Xis a nucleofugal leaving group, for example a halogen atom, for examplechlorine, bromine or iodine, or a sulphonyloxy group, for examplemethanesulphonyloxy or p-toluenesulphonyloxy.

If the imido nitrogen atom in compounds in which R₁ =hydrogen is not tobe alkylated, then it may, if necessary, be protected by one of thecustomary protecting groups mentioned above.

Further subsequent operations

The separation of resulting mixtures of isomers according to theinvention into pure isomers is effected in a manner known per se, forexample according to physical or chemical methods, for example byfractional crystallisation. It is also possible, however, to usechromatographic methods, for example solid-liquid chromatography.Readily volatile mixtures of isomers can also be separated bydistillation or by chromatography.

Acid addition salts are obtained in customary manner, for example bytreatment with an acid or a suitable anion exchange reagent.

The process relates also to those embodiments according to whichcompounds obtained as intermediates are used as starting materials andthe remaining process steps are carried out with these, or the processis interrupted at any stage; in addition, starting materials can be usedin the form of derivatives or can be formed during the reaction.

The starting materials used and the reaction conditions chosen arepreferably those which result in the compounds described above as beingespecially preferred.

Starting materials

The starting materials and intermediates used in the process for themanufacture of the compounds of the formula I of the present inventionare known or, if novel, can be manufactured in a manner known per se.The present invention relates also to novel intermediates and toprocesses for their manufacture.

Compounds of the formula II in which R₁ and R₄ have the meaningsmentioned under formula I and in which X represents a group that can beconverted into the group --N(R₂)(R₃), for example a nitrogen-containingreducible group, for example the nitro, nitroso, hydroxyamino or azidogroup, a replaceable group, for example halogen, for example chlorine,bromine or iodine, or a derivatised carboxy group, for example thecarbamoyl group or azidocarbonyl group, or a protected amino group arenovel and the present invention relates also to these. Preferredstarting materials of the formula II are compounds in which X representsa nitro group. Compounds of the formula II or salts thereof can bemanufactured in a manner known per se, for example, as follows:

(e) a compound of the formula ##STR7## in which R₄ has the meaning givenunder formula I and in which Y₁ and Y₂ represent leaving groups and X'represents one of the above-mentioned groups X or carboxy, or a saltthereof, is cyclised by reaction with a compound that yields the group--NH--R₁, or

(f) a compound of the formula ##STR8## in which R₁ ' represents a groupR₁ or an amino-protecting group and X' represents a group X or carboxy,and R₁, R₄ and X have the meanings given above, or a salt thereof, iscyclised, or

(g) a compound of the formula ##STR9## in which R₁ ' represents a groupR₁ or an amino-protecting group, X' represents a group X or carboxy andY₃ represents a leaving group, and R₁, R₄ and X have the meanings givenabove, or a salt thereof, is cyclised with a base, and in a resultingcompound the carboxy group X' is converted into a replaceable group, forexample carbamoyl or azidocarbonyl, and/or the amino-protecting group R₁' is removed and/or, if desired, a compound of the formula II obtainableaccording to the invention is converted into a different compound of theformula II according to the definition and/or a resulting salt isconverted into the free compound or into a different salt and/or aresulting free compound is converted into a salt and/or a resultingmixture of isomers is separated into the individual isomers.

Process (e) can be carried out under reaction conditions analogous tothose mentioned above under process (b); process (f) under reactionconditions analogous to those mentioned under process (c), and process(g) under reaction conditions analogous to those mentioned under process(d). The conversion of the carboxy group X' in a compound of the formulaII into an azidocarbonyl group or a carbamoyl group can be carried outin accordance with the derivatising processes for aromatic carboxygroups described in Organikum, VEB Deutscher Verlag der Wissenschaften,15th edition 1976. The removal of amino-protecting groups R₁ ' iscarried out in a manner analogous to that described under process (a).

Suitable amino-protecting groups R₁ ' and their removal are describedabove under process (a). Also suitable as amino-protecting groups R₁ 'are, for example, lower alkanoyl, for example acetyl or propionyl, orlower alkenoyl, for example acryloyl or, especially, methacryloyl. Theseprotecting groups are removed by acidolysis, for example using aceticacid, dichloroacetic acid, trifluoroacetic acid or dilute hydrochloricacid and the like. Also suitable as an amino-protecting group R₁ ' is,for example, 1-lower alkoxycarbonyl-1-alkenyl, for example1-methoxycarbonyl-1-vinyl. These protecting groups are removed byoxidation, for example using potassium permanganate, sodium periodateand a catalytic amount of osmium tetroxide, or ozone.

Compounds of the formula III and of the formula VII in which R₂, R₃ andR₄ have the meanings given under formula I, Y₁ and Y₂ represent leavinggroups and X' represents a group that can be converted into the group--N(R₂)(R₃), or carboxy, can be manufactured, for example, as follows:compounds of the formula ##STR10## in which R₄ has the meaning givenunder formula I and X" represents the group --N(R₂)(R₃), a group thatcan be converted into the group --N(R₂)(R₃), or carboxy, are alkylatedin the α-position in a manner analogous to that described by P. M.Warner et al. in J. Org. Chem. 46, 4795 (1981), using methylene iodideand lithium diisopropylamide, to form an ester function and thencyclised with a base in a manner analogous to that described in process(d) by removing hydrogen iodide, and, finally, the methoxy group of theester functions is optionally converted into a different leaving groupY₁ or Y₂.

Methods for converting a methoxy group of an ester into a leaving group,for example into hydroxy, chlorine, bromine, iodine or lower alkoxy, orinto an anhydride are described in Houben-Weyl, Vol. VIII,"Sauerstoffverbindungen III", Chapters 4 and 5.

Glutaric acid ester derivatives of the formula XI that are not alreadyknown can be obtained by methods analogous to that described in U.S.Pat. No. 2,824,120 from substituted phenylacetic acid esters andoptionally α-substituted acrylic esters.

Compounds of the formula IV and of the formula VIII in which R₁, R₂, R₃and R₄ have the meanings given under formula I, R₁ ' represents a groupR₁ or an amino-protecting group and X' represents a group that can beconverted into the group --N(R₂)(R₃), or carboxy, can be obtained in amanner analogous to that described by A. Alder et al. in Helv. Chim.Acta 65, 2405 (1982) and J. Am. Chem. Soc. 105, 6712 (1983) fromα-phenylacrylic acids substituted in the phenyl ring and acrylamidesoptionally substituted in the α-position and/or at the nitrogen atom.

Compounds of the formulae V and VI or of the formulae IX and X in whichR₁, R₂, R₃ and R₄ have the meanings given under formula I, R₁ 'represents a group R₁ or an amino-protecting group and X' represents agroup that can be converted into a group --N(R₂)(R₃), or carboxy can beobtained, for example, as follows: compounds of the formula ##STR11## inwhich R₁ ' and R₄ have the above-mentioned meanings and X" representsthe group --N(R₂)(R₃), a group that can be converted into the group--N(R₂)(R₃), or carboxy, are iodoalkylated in the α-position of acarbonyl function in a manner analogous to that described by P. M.Warner et al. in J. Org. Chem. 46, 4795 (1981) using methylene iodideand lithium diisopropylamide, or hydroxyalkylated in a correspondingmanner using formaldehyde and a non-nucleophilic base and the hydroxygroup is then converted in a manner known per se into halogen or asulphonyloxy group.

The ratio of the isomers of the formulae V and VI or IX and X formedduring this reaction is influenced by the nature of the substituents R₄and X", but is not of importance as, during the subsequent cyclisationaccording to process (d) or (g), uniform compounds of the formulae I andII, respectively, are formed.

Glutarimide derivatives of the formula XII that are not already knowncan be obtained from the corresponding glutaric acid ester derivative ofthe formula XI analogously to process (b) by reaction with a compoundthat introduces the radical >N--R₁ ', or can be manufactured byhydrogenating correspondingly substituted2-hydroxy-6-oxo-1,6-dihydropyridines of the formula ##STR12## or atautomeric compound thereof and then optionally alkylating or acylatingthe imido nitrogen atom using a compound that introduces the radical R₁'.

Compounds of the formula XIII are known or can be obtained in the mannerdescribed by E. Ziegler et al. in Z. Naturforsch 33b, 1550 (1978).

The following Examples serve to illustrate the invention but do notlimit the invention in any way. Temperatures are given in degreesCentigrade.

Abbreviations

IR=infra-red

The R_(f) values are determined on silica gel thin layer plates. R_(f)(CH₂ Cl₂) means, for example, that the R_(f) value is determined in theeluant CH₂ Cl₂ (methylene chloride).

EXAMPLE 1 (a)1-(4-aminophenyl)-3-n-propyl-3-azabicyclo[3.1.1]heptane-2,4-dione

0.35 g of 5% palladium-on-carbon catalyst is added to a solution of 3.5g of 1-(4-nitrophenyl)-3-n-propyl-3-azabicyclo3.1.1]heptane-2,4-dione in70 ml of ethyl acetate and the whole is hydrogenated under normalpressure and at 30°-35° in a hydrogen atmosphere. When the absorption ofhydrogen is complete, the reaction mixture is diluted with 30 ml ofmethylene chloride and freed of catalyst by filtration over HYFLOSuper-Cel®. The solvent is evaporated off in vacuo, and the residue isrecrystallised from a mixture of ethyl acetate/n-hexane, yielding thetitle compound in the form of white crystals having a melting point of166°-167°.

IR spectrum in CHCl₃ : 1685 and 1740 cm⁻¹ .

Manufacture of the starting material:

(b) 1-(4-nitrophenyl)-3-n-propyl-3-azabicyclo[3.1.1]heptane-2,4-dione

A solution of 46.1 g of4-aza-2-(4-nitrophenyl)-4-n-propyl-1,6-heptadiene- 3,5-dione and 0.5 gof 2,6-di-tert.-butyl-p-cresol in 900 ml of 1,3-dichlorobenzene isstirred at 170° for 11/2 hours. After concentration by evaporation theresidue is recrystallised from a methylene chloride/diisopropyl ethermixture, yielding the title compound in the form of pale yellow crystalshaving a melting point of 141°-143°. The mother liquor is concentratedby evaporation and filtered over silica gel 60 with methylene chloride.After recrystallisation from a methylene chloride/diisopropyl ethermixture, the resulting product yields white crystals having a meltingpoint of 149°-151°

IR spectrum in CHCl₃ :1350, 1685 and 1745 cm⁻¹.

(c) 4-aza-2-(4-nitrophenyl)-4-n-propyl-1,6-heptadiene-3,5-dione

A solution of 76.2 g of oxalyl chloride in 500 ml of methylene chlorideis added dropwise over a period of 2 hours at room temperature to astirred suspension of 115.8 g of α-(4-nitrophenyl)-acrylic acid in 5 mlof dimethylformamide and 2.5 liters of methylene chloride. When theaddition is complete, the mixture is stirred for a further 2 hours untilthe evolution of gas has ceased. The resulting solution of2-(4-nitrophenyl)-acrylic acid chloride is cooled to 0° and addeddropwise to a solution, cooled to 0°-5°, of 67.8 g ofN-n-propyl-acrylamide and 121 g of triethylamine in 450 ml of methylenechloride. When the addition is complete, the mixture is stirred for 11/2hours at room temperature. After concentration by evaporation, theresidue is stirred with 2 liters of ether and filtered with suction, andthe residue is again stirred with methylene chloride and again filteredwith suction. The ether filtrate is concentrated to dryness byevaporation in vacuo, and the residue is heated with 3 liters of hexane;activated carbon is added and the whole is filtered while hot. Aftercooling, the title compound is obtained in the form of pale pinkcrystals having a melting point of 68°-69.5°.

The methylene chloride filtrate is concentrated by evaporation to avolume of approximately 300 ml, filtered with suction and filtered over1.5 kg of silica gel 60 in ether. After the filtrate has beenconcentrated by evaporation and recrystallised from hexane there isobtained the title compound, likewise in crystalline form, having amelting point of 69°-70°. Repeat recrystallisation of the combinedproducts from hexane yields a white crystalline product having a meltingpoint of 71.5°-72.5°.

EXAMPLE 2 a)1-(4-aminophenyl)-3-methyl-3-azabicyclo[3.1.1]heptane-2,4-dione

In a manner analogous to that described in Example 1a, 6.0 g of3-methyl-1-(4-nitrophenyl)-3-azabicyclo[3.1.1]heptane-2,4-dione aredissolved in 120 ml of 2-methoxyethanol, hydrogenated in the presence of0.6 g of 5% palladium-on-carbon and worked up. Melting point 197°-198°(from ethyl acetate)

IR spectrum in CHCl₃ : 1680 and 1740 cm³¹ 1.

Manufacture of the starting material:

(b) 3-methyl-1-(4-nitrophenyl)-3-azabicyclo[3.1.1]-heptane-2,4-dione

In a manner analogous to that described in Example 1b, 37.1 g of4-aza-4-methyl-2-(4-nitrophenyl)-1,6-heptadiene-3,5-dione and 0.4 g of2,6-di-tert.-butyl-p-cresol in 370 ml of 1,3-dichlorobenzene are stirredat 170° and worked up. Melting point 185°-188° (from methylenechloride/diisopropyl ether).

IR spectrum in CHCl₃ : 1350, 1685 and 1740 cm⁻¹.

(c) 4-aza-4-methyl-2-(4-nitrophenyl)-1,6-heptadiene-3,5-dione

The title compound is prepared analogously to Example 1c starting from115.8 g of α-(4-nitrophenyl)-acrylic acid, 76.2 g of oxalyl chloride and51.1 g of N-methylacrylamide. The yellow oil is processed further incrude form.

EXAMPLE 3 (a)1-(4-aminophenyl)-3-isopropyl-3-azabicyclo[3.1.1]heptane-2,4-dione

In a manner analogous to that described in Example 1a, 2.3 g of3-isopropyl-1-(4-nitrophenyl)-3-azabicyclo[3.11]heptane-2,4-dione aredissolved in 50 ml of ethylacetate, hydrogenated in the presence of 0.25g of 5% palladium-on-carbon and worked up. Melting point 191°-201° (fromethyl acetate/hexane).

IR spectrum in CHCl₃ : 1680 and 1740 cm⁻¹.

Manufacture of the starting material:

(b) 3-isopropyl-1-(4-nitrophenyl)-3-azabicyclo[3.1.1]heptane-2,4-dione

In a manner analogous to that described in Example 1b, 10.2 g of4-aza-4-isopropyl-2-(4-nitrophenyl)-1,6-heptadiene-3,5-dione and 0.2 gof 2,6-di-tert.-butyl-p-cresol in 100 ml of 1,3-dichlorobenzene arestirred at 170° and worked up. R_(f) (CH₂ Cl₂)=1350, 1680 and 1740 cm⁻¹.

IR spectrum in CHCl₃ : 1350, 1680 and 1740 cm-1.

(c) 4-aza-4-isopropyl-2-(4-nitrophenyl)-1,6-heptadiene-3,5-dione

The title compound is prepared analogously to Example 1c starting from44.6 g of α-(4-nitrophenyl)-acrylic acid, 29.8 g of oxalyl chloride and21.8 g of N-isopropylacrylamide; oily solid. R_(f) (CH₂ Cl₂)=0.3.

EXAMPLE 4 (a)1-(4-aminophenyl)-3-neopentyl-3-azabicyclo[3.1.1]heptane-2,4-dione

In a manner analogous to that described in Example 1a, 4.1 g of3-neopentyl-1-(4-nitrophenyl)-3-azabicyclo[3.1.1]heptane-2,4-dione aredissolved in 80 ml of ethyl acetate, hydrogenated in the presence of 0.4g of 5% palladium-on-carbon and worked up. Melting point 141.5°-143°(from diethyl ether).

IR spectrum in CHCl₃ : 1685 and 1740 cm⁻¹.

Manufacture of the starting material:

(b) 3-neopentyl-1-(4-nitrophenyl)-3-azabicyclo[3.1.1]heptane-2,4-dione

In a manner analogous to that described in Example 1b, 12.1 g of4-aza-4-neopentyl-2-(4-nitrophenyl)-1,6-heptadiene-3,5-dione and 0.2 gof 2,6-di-tert.-butyl-p-cresol in 120 ml of 1,3-dichlorobenzene arestirred at 170° and worked up. After filtration over silica gel 60 withmethylene chloride, the title compound is obtained in the form of yellowcrystals having a melting point of 175°-182°. R_(f) (ether)=0.56.

IR spectrum in CHCl₃ : 1350, 1690 and 1745 cm⁻¹.

(c) 4-aza-4-neopentyl-2-(4-nitrophenyl)-1,6-heptadiene-3,5-dione

The title compound is prepared analogously to Example 1c starting from45.9 g of α-(4-nitrophenyl)-acrylic acid, 30.2 g of oxalyl chloride and28.0 g of N-neopentylacrylamide. Yellow oil R_(f) (CH₂ Cl₂)=0.36.

Alternative method of manufacturing the starting material:

(d) 3-neopentyl-1-(4-nitrophenyl)-3-azabicyclo [1.1.1]heptane-2,4-dione

2.4 ml of neopentylamine are added dropwise at room temperature to asuspension of 2.5 g of 1-(4-nitrophenyl)-1,3-cyclobutanedicarboxylicacid anhydride in 6 ml of acetic acid. The mixture is stirred at 120°for 20 hours. After concentration by evaporation, the residue ischromatographed over silica gel with a 2:1 ether/hexane mixture. Afraction is obtained that is identical with the title compound ofExample 4b.

(e) 1-(4-nitrophenyl)-1,3-cyclobutanedicarboxylic acid anhydride

A mixture of 10 g of cis-1-(4-nitrophenyl)-1,3-cyclobutanedicarboxylicacid and 100 ml of acetic anhydride is heated under reflux for 2 hours.The reaction mixture is concentrated to dryness by evaporation, and theresidue is suspended in toluene, filtered with suction, washed withether and dried overnight in vacuo. The title compound is obtained inthe form of grey crystals having a melting point of 183°-187°.

IR spectrum (KBr disc): 1355, 1780 and 1825 cm⁻¹.

(f) cis-1-(4-nitrophenyl)-1,3-cyclobutanedicarboxylic acid

A suspension of 36.3 g of1-(4-nitrophenyl)-3-n-propyl-3-azabicyclo-[3.1.1]-heptane-2,4-dione, 250ml of acetic acid and 500 ml of 50% sulphuric acid is stirred at 140°for 20 hours. After cooling, the suspension is poured onto ice andextracted four times with ether. The ether extracts are washed twicewith aqueous sodium chloride solution, dried with magnesium sulphate andconcentrated by evaporation. Toluene is added to the residue and thewhole is again concentrated by evaporation in vacuo. Afterrecrystallisation from ethyl acetate there are obtained white crystalshaving a melting point of 218°-219°.

EXAMPLE 5 (a)1-(4-aminophenyl)-3-n-decyl-3-azabicyclo[3.1.1]heptane-2,4-dione

In a manner analogous to that described in Example 1a, 6.0 g of3-n-decyl-1-(4-nitrophenyl)-3-azabicyclo[3.1.1]heptane-2,4-dione aredissolved in 120 ml of 2-methoxyethanol, hydrogenated in the presence of0.6 g of 5% palladium-on-carbon and worked up. Melting point 81.5°-82.5°(from ethyl acetate/hexane).

IR spectrum in CHCl₃ : 1680 and 1740 cm⁻¹.

Manufacture of the starting material:

(b) 3-n-decyl-1-(4-nitrophenyl)-3-azabicyclo[3.1.1]-heptane-2,4-dione

In a manner analogous to that described in Example 1b, 36.5 g of4-aza-4-n-decyl-2-(4-nitrophenyl)-1,6-heptadiene-3,5-dione and 0.4 g of2,6-di-tert.-butyl-p-cresol in 370 ml of 1,3-dichlorobenzene are stirredat 170° and worked up. After filtration over silica gel 60 with anether/hexane mixture 1:1, the title compound is obtained in the form ofa yellow oil. R_(f) (ether)=0.54.

IR spectrum in CHCl₃ : 1350, 1685 and 1740 cm⁻¹.

(c) 4-aza-4-n-decyl-2-(4-nitrophenyl)-1,6-heptadiene-3,5-dione

The title compound is prepared analogously to Example 1c starting from37.8 g of α-(4-nitrophenyl)-acrylic acid, 24.9 g of oxalyl chloride and41.7 g of N-n-decylacrylamide. Yellow oil.

EXAMPLE 6 (a)1-(4-aminophenyl)-3-cyclohexylmethyl-3-azabicyclo[3.1.1]heptane-2,4-dione

In a manner analogous to that described in Example 1a, 6.0 g of3-cyclohexylmethyl-1-(4-nitrophenyl)-3-azabicyclo[3.1.1]heptane-2,4-dioneare dissolved in 120 ml of 2-methoxyethanol, hydrogenated in thepresence of 0.6 g of 5% palladium-on-carbon and worked up. Melting point140°-146° (from ether) R_(f) (ether)=0.25.

IR spectrum in CHCl₃ : 1685 and 1740 cm⁻¹.

Manufacture of the starting material:

3-cyclohexylmethyl-1-(4-nitrophenyl)-3-azabicyclo[3.1.1]heptane-2,4-dione

In a manner analogous to that described in Example 1b, 22.3 g of4-aza-4-cyclohexylmethyl-2-(4-nitrophenyl)-1,6-heptadiene-3,5-dione and0.3 g of 2,6-di-tert.-butyl-p-cresol in 220 ml of 1,3-dichlorobenzeneare stirred at 170° and worked up. Melting point 191°-194° (frommethylene chloride/diisopropyl ether)

IR spectrum in CHCl₃ : 1350, 1685 and 1740 cm⁻¹.

(c) 4-aza-4-cyclohexylmethyl-2-(4-nitrophenyl)-1,6-heptadiene-3,5-dione

The title compound is prepared analogously to Example 1c starting from47.9 g of α-(4-nitrophenyl)-acrylic acid, 31.5 g of oxalyl chloride and34.7 g of N-cyclohexylmethylacrylamide; light yellow crystals having amelting point of 92°-93°.

EXAMPLE 7 (a)1-(4-aminophenyl)-3-cyclohexyl-3-azabicyclo[3.1.1]heptane-2,4-dione

In a manner analogous to that described in Example 1a, 6.0 g of3-cyclohexyl-1-(4-nitrophenyl)-3-azabicyclo[3.1.1]heptane-2,4-dione aredissolved in 120 ml of 2-methoxyethanol, hydrogenated in the presence of0.6 g of 5% palladium-on-carbon and worked up. Melting point 139°-140°(from ether).

IR spectrum in CHCl₃ : 1680 and 1735 cm⁻¹.

Manufacture of the starting material:

(b) 3-cyclohexyl-1-(4-nitrophenyl)-3-azabicyclo[3.1.1]heptane-2,4-dione

In a manner analogous to that described in Example 1b, 34.6 g of4-aza-4-cyclohexyl-2-(4-nitrophenyl)-1,6-heptadiene-3,5-dione and 0.4 gof 2,6-di-tert.-butyl-p-cresol in 350 ml of 1,3-dichlorobenzene arestirred at 170° and worked up. Melting point 163°-164° (from methylenechloride/diisopropyl ether).

IR spectrum in CHCl₃ : 1350, 1690 and 1745 cm⁻¹.

(c) 4-aza-4-cyclohexyl-2-(4-nitrophenyl)-1,6-heptadiene-3,5-dione

The title compound is prepared analogously to Example 1c starting from40.5 g of a-(4-nitrophenyl)-acrylic acid, 26.7 g of oxalyl chloride and26.8 g of N-cyclohexylacrylamide. Melting point 73°-74° (from hexane).

EXAMPLE 8 (a)1-(4-aminophenyl)-3-(4-methoxybenzyl)-3-azabicyclo[3.1.1]heptane-2,4-dione

In a manner analogous to that described in Example 1a, 5.0 g of3-(4-methoxybenzyl)-1-(4-nitrophenyl)-3-azabicyclo[3.1.1]heptane-2,4-dioneare dissolved in 100 ml of ethyl acetate, hydrogenated in the presenceof 1 g of 5% palladium-on-carbon and worked up. Melting point147°-147.5° (from ether).

IR spectrum in CHCl₃ : 1680 and 1735 cm⁻¹.

Manufacture of the starting material:

(b)3-(4-methoxybenzyl)-1-(4-nitrophenyl)-3-azabicyclo[3.1.1]heptane-2,4-dione

In a manner analogous to that described in Example 1b, 78.2 g of4-aza-4-(4-methoxybenzyl)-2-(4-nitrophenyl)-1,6-heptadiene-3,5-dione and0.3 g of 2,6-di-tert.-butyl-p-cresol in 700 ml of 1,3-dichlorobenzeneare stirred at 170° and worked up. Melting point 146°-147° (fromtoluene/ether).

IR spectrum in CHCl₃ : 1350, 1685 and 1745 cm⁻¹.

(c) 4-aza-4-(4-methoxybenzyl)-2-(4-nitrophenyl)-1,6-heptadiene-3,5-dione

The title compound is prepared analogously to Example 1c starting from106.1 g of α-(4-nitrophenyl)-acrylic acid, 76.8 g of oxalyl chloride and95.5 g of N-(4-methoxybenzyl)-acrylamide. Melting point 106.5°-107°(from other).

EXAMPLE 9 (a) 1-(4-aminophenyl)-3-azabicyclo[3.1.1]heptane-2,4-dione

In a manner analogous to that described in Example 1a, 5.0 g of1-(4-nitrophenyl)-3-azabicyclo[3.1.1]heptane-2,4-dione in 250 ml of2-methoxyethanol are hydrogenated at 45° in the presence of 0.5 g of 5%palladium-on-carbon and worked up. The title compound is obtained which,after recrystallisation from 2-methoxyethanol, melts at 265° withdecomposition.

IR spectrum (KBr disc): 1700 and 1735 cm⁻¹.

Manufacture of the starting material:

(b) 1-(4-nitrophenyl)-3-azabicyclo[3.1.1]heptane-2,4-dione

A solution of 283 g of cerium(IV) ammonium nitrate in 400 ml of water isadded dropwise at room temperature to a stirred solution of 50 g of3-(4-methoxybenzyl)-1-(4-nitrophenyl)-3-azabicyclo[3.1.1]heptane-2,4-dionein 1.3 liters of acetonitrile.

When the addition is complete, the mixture is stirred for a further 4hours. The resulting emulsion is concentrated to half the volume invacuo and then diluted with 2 liters of water. The product formed isfiltered with suction, washed with water and dried in vacuo. The crudeproduct is then dissolved in 3 liters of hot acetonitrile, and theresulting solution is filtered over HYFLO Super-Cel® and the filtrate isconcentrated at 60°-70° under a water-jet vacuum until crystallisationbegins. The title compound is obtained in the form of brownish crystalshaving a melting point of above 250°.

IR spectrum (KBr disc): 1355, 1695 and 1720 cm⁻¹.

EXAMPLE 10 (a)1-(4-aminophenyl)-3-benzyl-3-azabicyclo[3.1.1]heptane-2,4-dione

In a manner analogous to that described in Example 1a, 2.46 g of3-benzyl-1-(4-nitrophenyl)-3-azabicyclo[3.1.1]heptane-2,4-dione aredissolved in 50 ml of ethyl acetate, hydrogenated in the presence of 0.3g of 5% palladium-on-carbon and worked up. Melting point 164°-165.5°(from ether/ethyl acetate).

IR spectrum in CHCl₃ : 1690 and 1745 cm⁻¹.

Manufacture of the starting material:

(b) 3-benzyl-1-(4-nitrophenyl)-3-azabicyclo[3.1.1]heptane-2,4-dione

4.92 g of 1-(4-nitrophenyl)-3-azabicyclo[3.1.1]heptane-2,4-dione aredissolved in 70 ml of dimethylformamide and, under a nitrogenatmosphere, 1.2 g of sodium hydride (pract. Fluka) are added. Afterstirring for 30 minutes at room temperature, the mixture is cooled to0°, and a solution of 4.5 g of benzyl bromide in 10 ml ofdimethylformamide is added dropwise thereto. After the addition iscomplete, the mixture is stirred at room temperature for 4 hours. Theexcess sodium hydride is destroyed by the addition of methanol, andconcentration by evaporation is effected in vacuo. The residue is takenup in ethyl acetate and washed with water and aqueous sodium chloridesolution. After drying over magnesium sulphate, the mixture is filteredand concentrated by evaporation. Melting point 150°-152° (from ether).

IR spectrum in CHCl₃ : 1355, 1690 and 1745 cm⁻¹.

EXAMPLE 11 (a)1-(4-aminophenyl)-3-cyclohexylmethyl-3-azabicyclo[3.1.1]heptane-2,4-dione

2.4 of cis-1-(4-aminophenyl)-1,3-cyclobutanedicarboxylic acid and 1.3 mlof cyclohexylmethylamine are stirred in 100 ml of xylene at 140° for 24hours in a water separator. The reaction mixture is concentrated todryness by evaporation in vacuo and then chromatographed over silica gelwith ether. The crystalline fraction is identical with the titlecompound of Example 6a.

Manufacture of the starting material:

(b) cis-1-(4-aminophenyl)-1,3-cyclobutanedicarboxylic acid

5 g of cis-1-(4-nitrophenyl)-1,3-cyclobutanedicarboxylic acid aredissolved in 170 ml of 2-methoxyethanol and hydrogenated in the presenceof 0.5 g of 5% palladium-on-carbon. After filtration through HYFLOSuper-Cel®, concentration by evaporation is carried out. Light yellowcrystals. Melting point 228°-229° (decomposition).

EXAMPLE 12 (a)1-(4-aminophenyl)-5-methyl-3-n-propyl-3-azabicyclo[3.1.1]heptane-2,4-dione

1.0 g of 5% palladium-on-carbon catalyst is added to a solution of 10.0g of5-methyl-1-(4-nitrophenyl)-3-n-propyl-3-azabicyclo3.1.1]heptane-2,4-dionein 200 ml of ethyl acetate and the whole is hydrogenated under normalpressure and at 30°-35° in a hydrogen atmosphere. When the absorption ofhydrogen is complete, the reaction mixture is diluted with 100 ml ofmethylene chloride and freed of catalyst by filtration over HYFLOSuper-Cel®. The solvent is evaporated off in vacuo, and the residue isrecrystallised from an ethyl acetate/n-hexane mixture, yielding thetitle compound in the form of white crystals having a melting point of135°-136°.

IR spectrum in CHCl₃ : 1685 and 1740 cm⁻¹.

Manufacture of the starting material:

(b)5-methyl-1-(4-nitrophenyl)-3-n-propyl-3-azabicyclo[3.1.1]heptane-2,4-dione

While stirring, a solution of 23.0 g of4-aza-6-methyl2-(4-nitrophenyl)-4-n-propyl-1,6-heptadiene-3,5-dione and0.23 g of 2,6-di-tert.-butyl-p-cresol in 2.3 liters of acetone isirradiated for 3 hours using a UV lamp (Philips 125 HPK) which isimmersed in the reaction solution in a double-walled, water-cooled Pyrexglass shaft. After concentration by evaporation, the residue isrecrystallised from a methylene chloride/diisopropyl ether mixture,yielding the title compound in the form of white crystals having amelting point of 128.5°-129.5°.

IR spectrum in CHCl₃ : 1350, 1685 and 1745 cm⁻¹.

(c) 4-aza-6-methyl-2-(4-nitrophenyl)-4-n-cropyl-1,6-heptadiene-3,5-dione

A solution of 15.3 g of oxalyl chloride in 100 ml of methylene chlorideis added dropwise over a period of 30 minutes at room temperature to astirred suspension of 23.2 g of α-(4-nitrophenyl)-acrylic acid in 1 mlof dimethylformamide and 600 ml of methylene chloride. When the additionis complete, stirring is continued for a further 30 minutes until theevolution of gas has ceased. The resulting solution ofα-(4-nitrophenyl)-acrylic acid chloride is cooled to 0° and addeddropwise to a solution, cooled to 0°-5°, of 15.2 g ofN-n-propylmethacrylamide and 24.2 g of triethylamine in methylenechloride (100 ml). When the addition is complete, the mixture is stirredat room temperature for 1.5 hours. After concentration by evaporation invacuo, the residue is stirred with ether, then filtered and concentratedby evaporation.

The residue is stirred with boiling hexane; activated carbon is addedand the mixture is filtered while hot. The flltrate is concentrated byevaporation, and the residue is recrystallised from diisopropyl ether.The pale yellow crystalline title compound has a melting point of62°-63°.

EXAMPLE 13 (a)1-(4-aminophenyl)-5-ethyl-3-n-propyl-3-azabicyclo[3.1.1]heptane-2.4-dione

In a manner analogous to that described in Example 12a, 6.3 g of5-ethyl-1-(4-nitrophenyl)-3-n-propyl-3-azabicyclo[3.1.1]-heptane-2,4-dioneare dissolved in 120 ml of ethyl acetate, hydrogenated in the presenceof 0.6 g of 5% palladium-on-carbon and worked up. Melting point124.5°-125° (from ether).

IR spectrum in CHCl₃ : 1685 and 1740 cm⁻¹.

Manufacture of the starting material:

(b)5-ethyl-1-(4-nitrophenyl)-3-n-propyl-3-azabicyclo[3.1.1]heptane-2,4-dione

In a manner analogous to that described in Example 1b, 29.6 g of4-aza-6-ethyl-2-(4-nitrophenyl)-4-n-propyl-1,6-heptadiene-3,5-dione and0.27 g of 2,6-di-tert.-butyl-p-cresol in 560 ml of 1,3-dichlorobenzeneare stirred at 170° and worked up. Melting point 121°-122° (fromdiisopropyl ether).

IR spectrum in CHCl₃ : 1350, 1685 and 1740 cm⁻¹.

(c) 4-aza-6-ethyl-2-(4-nitrophenyl)-4-n-propyl-1,6-heptadiene-3,5-dione

The title compound is prepared analogously to Example 12c starting from34.7 g of α-(4-nitrophenyl)-acrylic acid, 22.8 g of oxalyl chloride and26 g of N-n-propyl-α-ethylacrylamide. Yellow oil. R_(f) (n-hexane/ether1:1)=0.46.

EXAMPLE 14 (a)1-(4-aminophenyl)-5-isobutyl-3-n-propyl-3-azabicyclo[3.1.1]heptane-2,4-dione

In a manner analogous to that described in Example 12a, 5.2 g of5-isobutyl-1-(4-nitrophenyl)-3-n-propyl-3-azabicyclo[3.1.1]heptane-2,4-dionein 100 ml of ethyl acetate are hydrogenated in the presence of 0.5 g of5% palladium-on-carbon and worked up. Melting point 86.5°-87° (fromn-hexane/ether).

IR spectrum in CHCl₃ : 1690 and 1740 cm⁻¹.

Manufacture of the starting material:

(b)5-isobutyl-1-(4-nitrophenyl)-3-n-propyl-3-azabicyclo[3.1.1]heptane-2,4-dione

In a manner analogous to that described in Example 12b, 20.7 g of4-aza-6-isobutyl-2-(4-nitrophenyl)-4-n-propyl-1,6-heptadiene-3,5-dioneare irradiated in the presence of 0.2 g of 2,6-di-tert.-butyl-p-cresolin 1.5 liters of acetone. The reaction product is concentrated byevaporation and then chromatographed over silica gel with n-hexane/ether1:1. Melting point 87°-88° (from n-hexane/ether).

IR spectrum in CHCl₃ : 1355, 1690 and 1740 cm⁻¹.

(c)4-aza-6-isobutyl-2-(4-nitrophenyl)-4-n-prooyl-1,6-heptadiene-3,5-dione

The title compound is prepared analogously to Example 12c starting from16.4 g of α-(4-nitrophenyl)-acrylic acid, 10.7 g of oxalyl chloride and14.4 g of N-n-propyl-α -isobutylacrylamide; yellow oil.

EXAMPLE 15 (a)1-(4-aminophenyl)-5-phenyl-3-n-propyl-3-azabicyclo[3.1.1]heptane-2,4-dione

In a manner analogous to that described in Example 12a, 1.8 g of1-(4-nitrophenyl)-5-phenyl-3-n-propyl-3-azabicyclo[3.1.1]heptane-2,4-dioneare dissolved in 40 ml of ethyl acetate, hydrogenated in the presence of0.2 g of 5% palladium-on-carbon and worked up. Melting point 144°-145°(from n-hexane/ether).

IR spectrum in CHCl₃ : 1685 and 1735 cm⁻¹.

Manufacture of the starting material:

(b)1-(4-nitrophenyl)-5-phenyl-3-n-propyl-3-azabicyclo[3.1.1]heptane-2,4-dione

In a manner analogous to that described in Example 12b, 3.6 g of4-aza-2-(4-nitrophenyl)-6-phenyl-4-n-propyl-1,6-heptadiene-3,5-dione areirradiated in the presence of 0.04 g of 2,6-di-tert.-butyl-p-cresol in250 ml of acetone. The reaction product is concentrated by evaporationand then chromatographed over silica gel with toluene/ethyl acetate15:1. Melting point 144°-146° (from toluene/ether).

IR spectrum in CHCl₃ : 1350, 1695 and 1745 cm⁻¹.

(c) 4-aza-2-(4-nitrophenyl)-6-phenyl-4-n-propyl-1,6-heptadiene-3,5-dione

The title compound is prepared analogously to Example 12c starting from36.7 g of α-(4-nitrophenyl)-acrylic acid, 24.1 g of oxalyl chloride and35.8 g of N-n-propyl-α-phenylacrylamide; white crystals having a meltingpoint of 98°-99°.

EXAMPLE 16 (a)1,5-di-(4-aminophenyl)-3-n-propyl-3-azabicyclo[3.1.1]heptane-2,4-dione

In a manner analogous to that described in Example 12a, 0.4 g of1,5-di-(4-nitrophenyl)-3-n-propyl-3-azabicyclo[3.1.1]heptane-2,4-dioneare dissolved in 15 ml of ethyl acetate, hydrogenated in the presence of80 mg of 5% palladium-on-carbon and worked up. Melting point 149°-150°(from ether/methylene chloride).

IR spectrum in CHCl₃ : 1685 and 1735 cm⁻¹.

Manufacture of the starting material:

(b)1,5-di-(4-nitrophenyl)-3-n-propvl-3-azabicyclo[3.1.1]heptane-2,4-dione

In a manner analogous to that described in Example 1b, 6 g of4-aza-2,6-di-(4-nitrophenyl)-4-n-propyl-1,6-heptadiene-3,5-dione and0.08 g of 2,6-di-tert -butyl-p-cresol in 85 ml of 1,3-dichlorobenzeneare stirred at 170° and worked up. Column chromatography of the crudeproduct over silica gel with toluene/ethyl acetate 4:1 yields the titlecompound which, after recrystallisation from a toluene/ether mixture,melts at 237°-238°.

IR spectrum in CHCl₃ : 1350, 1690 and 1740 cm⁻¹.

(c) 4-aza-21,6-di-(4-nitroohenyl)-4-n-propyl-1,6-heptadiene-3,5-dione

The title compound is prepared analogously to Example 12c starting from19.3 g of α-(4-nitrophenyl)-acrylic acid, 12.7 g of oxalyl chloride and18 g of N-n-propyl-α-(4-nitro-phenyl)-acrylamide. White crystals havinga melting point of 177°-175°.

EXAMPLE 17 (a)1-(4-aminophenyl)-5-methyl-3-azabicyclo[3.1.1]heptane-2,4-dione

In a manner analogous to that described in Example 12a, 3.7 g of5-methyl-1-(4-nitrophenyl)-3-azabicyclo.3.1.1heptane-2,4-dione in 80 mlof 2-methoxyethanol are hydrogenated in the presence of 0.4 g of 5%palladium-on-carbon and worked up. Melting point 216° (from ethanol).

IR spectrum in CHCl₃ : 1715 and 1745 cm⁻¹.

Manufacture of the starting material:

(b) 5-methyl-1-(4-nitrophenyl)-3-azabicyclo[3.1.1]heptane-2,4-dione

At 60°, ammonia is introduced into a stirred suspension of 0.9 g3-methyl-1-(4-nitrophenyl)-1,3-cyclobutanedicarboxylic acid anhydride in50 ml of 1,3-dichlorobenzene. After the amido acid has formed, themixture is heated at reflux for 8 hours, and the reaction solution isthen filtered with suction while hot. On cooling, the title compound isformed in the form of brownish-yellow crystals. Melting point 242°-244°(from ethyl acetate).

IR spectrum (KBr disc): 1360, 1700 and 1745 cm⁻¹.

(c) 3-methyl-1-(4-nitrophenyl)-1,3-cyclobutanedicarboxylic acidanhydride

A mixture of 10 g ofcis-3-methyl-1-(4-nitrophenyl)-1,3-cyclobutanedicarboxylic acid and 100ml of acetic anhydride is heated under reflux for 2 hours. The reactionmixture is concentrated to dryness by evaporation, and the residue issuspended in toluene, filtered with suction, washed with ether and driedin vacuo. The title compound is obtained in the form of grey crystalshaving a melting point of 201°-202°.

IR spectrum (KBr disc): 1350, 1765 and 1820 cm⁻¹.

(d) cis-3-methyl-1-(4-nitrophenyl)-1,3-cyclobutanedicarboxylic acid

A suspension of 46 g of5-methyl-1-(4-nitrophenyl)-3-n-propyl-3-azabicyclo[3.1.1]heptane-2,4-dione,250 ml of acetic acid and 500 ml of 50% sulphuric acid is stirred for 20hours at 140°. After cooling, the suspension is poured onto ice andextracted three times with ether. The ether extracts are washed withwater, dried with magnesium sulphate and concentrated by evaporation.The title compound is obtained by recrystallisation from ethyl acetate.Melting point 231° (decomposition).

EXAMPLE 181(4-acetylaminophenyl)-3-n-propyl-3-azabicyclo[3.1.1]heptane-2,4-dione

A solution of 0.11 ml of acetic anhydride in 0.5 ml of tetrahydrofuranis added dropwise to a solution of 260 mg of1-(4-aminophenyl)-3-n-propyl-3-azabicyclo[3.1.1heptane-2,4-dione and 6mg of 4-dimethylaminopyridine in 8 ml of tetrahydrofuran. After stirringat room temperature for 21/2 hours, two drops of ethanol are added tothe reaction mixture and stirring is continued for a further 15 minutes.After concentration by evaporation and subsequent recrystallisation fromethyl acetate/petroleum ether, the title compound is obtained in theform of white crystals having a melting point of 138.5-139.5°. R_(f)(methylene chloride/methanol/glacial acetic acid 40:5:1)=0.55.

EXAMPLE 19 1-(4-dimethylaminophenyl)- and1-(4-methylaminophenyl)-3-n-propyl-3-azabicyclo[3.1.1]heptane-2,4-dione

While stirring, a solution of 15 ml of dimethyl sulphate in 60 ml oftetrahydrofuran is added to a solution of 20.3 g of1-(4-aminophenyl)-3-n-propyl-3-azabicyclo[3.1.1]heptane-2,4-dione in 470ml of tetrahydrofuran. A solution of 21.9 ml of triethylamine in 40 mlof tetrahydrofuran is then added dropwise, while stirring, over a periodof 6 hours. After stirring for a further 10 hours, 2.5 ml of 15% aqueousammonia solution is added to the reaction mixture. After concentrationby evaporation, water is added to the residue, and extraction is carriedout with methylene chloride. The organic phase is separated off, driedover magnesium sulphate, filtered and concentrated by evaporation. Afterchromatography over silica gel with hexane/ethyl acetate 2:1 there isobtained1-(4-dimethylaminophenyl)-3-n-propyl-3-azabicyclo[3.1.1]heptane-2,4-dione,R_(f) (hexane/ethyl acetate 1:1)=0.45, melting point 139°-140° C. (fromethanol); and1-(4-methylaminophenyl)-3-n-propyl-3-azabicyclo[3.1.1]heptane-2,4-dione,R_(f) (hexane/ethyl acetate 1:1)=0.35, melting point 134°-135° (fromethanol).

EXAMPLE 201-(4-N-acetyl-N-methylaminophenyl)-3-n-propyl-3-azabicyclo[3.1.1]heptane-2,4-dione

A mixture of 272 mg of1-(4-N-methylaminophenyl)-3-n-propyl-3-azabicyclo[3.1.1]heptane-2,4-dione,10 ml of tetrahydrofuran, 6 mg of 4-dimethylaminopyridine and 0.11 ml ofacetic anhydride is stirred at room temperature for 2 hours. Two dropsof methanol are then added to the reaction mixture, which is thenstirred for a further 15 minutes and concentrated by evaporation. Theresidue is partitioned twice between ethyl acetate and water. Thecombined organic phases, dried over MgSO₄, are filtered and concentratedby evaporation. The oily residue is crystallised from ethylacetate/petroleum ether. The title compound is obtained in the form ofwhite crystals having a melting point of 144°-146°. R_(f) (methylenechloride/methanol 10:1)=0.55.

EXAMPLE 211-(4-methanesulphonylaminophenyl)-3-n-propyl-3-azabicyclo[3.1.1]heptane-2,4-dione

A solution of 0.31 ml of methanesulphonic acid chloride in 3 ml ofmethylene chloride is added at room temperature to a solution of 1.03 gof 1-(4-aminophenyl)-3-n-propyl-3-azabicyclo[3.1.1]heptane-2,4-dione and24 mg of 4-dimethylaaminopyridine in 10 ml of pyridine. After stirringfor 5 hours, 50 ml of water are added, and the mixture is left to standovernight at 0°-5°. Extraction is carried out with methylene chloride,and the organic phase is washed in succession with water, cold 2Nhydrochloric acid, water, semi-saturated bicarbonate solution and water.After drying over magnesium sulphate, the mixture is filtered andconcentrated by evaporation, and the residue is recrystallised frommethanol. The title compound is obtained in the form of white crystalshaving a melting point of 159°-160°. R_(f) (hexane/ethyl acetate1:1)=0.15.

EXAMPLE 22 (a)1-(4-aminophenyl)-3-ethyl-3-azabicyclo[3.1.1]heptane-2,4-dione

In a manner analogous to that described in Example 1a, 2.33 g of3-ethyl-1-(4-nitrophenyl)-3-azabicyclo[3.1.1-]heptane-2,4-dione in 70 mlof methanol are hydrogenated in the presence of 0.15 g ofpalladium-on-carbon and worked up. Melting point 159°-162° (from ethylacetate/petroleum ether).

Manufacture of the starting material:

(b) 3-ethyl-1-(4-nitrophenyl)-3-azabicyclo[3.1.1]heptane-2,4-dione

0.36 g of sodium hydride is added to a solution of 2.46 g of1-(4-nitrophenyl)-3-azabicyclo[3.1.1]heptane-2,4-dione in 25 ml ofN,N-dimethylformamide and the whole is stirred at room temperature for30 minutes. 2.33 g of ethyl iodide dissolved in 10 ml ofN,N-dimethylformamide are then added dropwise thereto. When the reactionis complete, the reaction mixture is freed of N,N-dimethylformamide. Theresidue is partitioned between ethyl acetate and water, and the organicphase is dried over magnesium sulphate and, after concentration byevaporation, the product is obtained in the form of a solid. Meltingpoint 175°-179°. R_(f) (ethyl acetate/hexane 4:1)=0.52.

EXAMPLE 23 (a)1-(4-aminophenyl)-3-n-butyl-3-azabicyclo[3.1.1]heptane-2,4-dione

In a manner analogous to that described in Example 1, 2.08 g of3-n-butyl-1-(4-nitrophenyl)-3-azabicyclo[3.1.1heptane-2,4-dione in 60 mlof ethanol ar the presence of 0.15 g of palladium-on-carbon and workedup. Melting point 178°-179° (from ethyl acetate).

Manufacture of the starting material:

(b) 3-n-butyl-1-(4-nitrophenyl)-3-azabicyclo[3.1.1]heptane-2,4-dione

0.36 g of sodium hydride is added to a solution of 2.46 g of1-(4-nitrophenyl)-3-azabicyclo[3.1.1]heptane-2,4-dione in 25 ml ofN,N-dimethylformamide and the whole is stirred at room temperature for30 minutes. 1.6 ml of n-butyl bromide dissolved in 10 ml ofN,N-dimethylformamide are then added dropwise thereto. When the reactionis complete, the reaction mixture is freed of N,N-dimethylformamide. Theresidue is partitioned between ethyl acetate and water, and the organicphase is dried over magnesium sulphate and, after concentration byevaporation and subsequent recrystallisation from ethylacetate/petroleum ether, the product is obtained having a melting pointof 120°-123°.

EXAMPLE 24 (a)1-(4-aminophenyl)-3-isobutyl-3-azabicyclo[3.1.1]heptane-2,4-dione

In a manner analogous to that described in Example 1, 2.0 g of3-isobutyl-1-(4-nitrophenyl)-3-azabicyclo[3.1.1]heptane-2,4-dione in 100ml of ethanol are hydrogenated in the presence of 0.1 g ofpalladium-on-carbon and worked up. Melting point 158°-160° (from ethylacetate/petroleum ether).

Manufacture of the starting material:

(b) 3-isobutyl-1-(4-nitrophenyl)-3-azabicyclo[3.1.1]heptane-2,4-dione

0.36 g of sodium hydride is added to a solution of 2.46 g of1-(4-nitrophenyl)-3-azabicyclo[3.1.1]heptane-2,4-dione in 25 ml ofN,N-dimethylformamide and the whole is stirred at room temperature for30 minutes. 2.76 g of isobutyl iodide dissolved in 10 ml ofN,N-dimethylformamide are then added dropwise thereto. When the reactionis complete, the reaction mixture is freed of N,N-dimethylformamide. Theresidue is partitioned between ethyl acetate and water, and the organicphase is dried over magnesium sulphate and, after concentration byevaporation and purification by chromatography over silica gel in thesystem ethyl acetate/hexane 1:2, the product is obtained in the form ofa solid. Melting point 136°-137°. R_(f) (ethyl acetate/hexane 4:1)=0.6.

EXAMPLE 25 (a)1-(4-aminophenyl)-3-n-pentyl-3-azabicyclo[3.1.1]heptane-2,4-dione

In a manner analogous to that described in Example 1, 2.58 g of1-(4-nitrophenyl)-3-n-pentyl-3-azabicyclo[3.1.1]heptane-2,4-dione in 75ml of ethanol are hydrogenated in the presence of 0.15 g ofpalladium-on-carbon and worked up. Melting point 92°-94° (from ethylacetate/petroleum ether).

Manufacture of the starting material:

(b) 1-(4-nitrophenyl)-3-n-pentyl-3-azabicyclo[3.1.1]heptane-2,4-dione

0.36 g of sodium hydride is added to a solution of 2.46 g of1-(4-nitrophenyl)-3-azabicyclo[3.1.1]heptane-2,4-dione in 25 ml ofN,N-dimethylformamide and the whole is stirred at room temperature for30 minutes. 2.96 g of n-pentyl iodide dissolved in 10 ml ofN,N-dimethylformamide are then added dropwise thereto. When the reactionis complete, the reaction mixture is freed of N,N-dimethylformamide. Theresidue is partitioned between ethyl acetate and water, and the organicphase is dried over magnesium sulphate and, after concentration byevaporation, the product is obtained having a melting point of 75°-79°.

EXAMPLE 26 (a)1-(4-aminophenyl)-3-n-heptyl-3-azabicyclo[3.1.1]heptane-2,4-dione

In a manner analogous to that described in Example 1, 2.1 g of3-n-heptyl-1-(4-nitrophenyl)-3-azabicyclo[3.1.1]heptane-2,4-dione in 100ml of ethanol are hydrogenated in the presence of 0.1 g ofpalladium-on-carbon and worked up. After purification by columnchromatography on silica gel with the system hexane/ethyl acetate 1:1,the title compound is obtained in the form of wax-like crystals. Meltingpoint 69°-71°, R_(f) (hexane/ethyl acetate 1:1)=0.25.

Manufacture of the starting material:

(b) 3-n-heptyl-1-(4-nitrophenyl)-3-azabicyclo[3.1.1]heptane-2,4-dione

0.36 g of sodium hydride is added to a solution of 2.46 g of1-(4-nitrophenyl)-3-azabicyclo[3.1.1]heptane-2,4-dione in 25 ml ofN,N-dimethylformamide and the whole is stirred at room temperature for30 minutes. 2.68g of n-heptyl bromide dissolved in 10 ml ofN,N-dimethylformamide are then added dropwise thereto. When the reactionis complete, the reaction mixture is freed of N,N-dimethylformamide. Theresidue is partitioned between ethyl acetate and water, and the organicphase is dried over magnesium sulphate. After concentration byevaporation and purification by chromatography over silica gel in thesystem ethyl acetate/hexane 2:5, the product is obtained in the form ofa solid. Melting point 91°-92°. R_(f) (ethyl acetate/hexane 4:1)=0.63.

EXAMPLE 27 (a)3-allyl-1-(4-aminophenyl)-3-azabicyclo[3.1.1]heptane-2,4-dione

A mixture of 1.97 g of3-allyl-1-(4-nitrophenyl)-3-azabicyclo-3.1.1]heptane-2,4-dione and 5.2 gof tin powder in 14 ml of water and 14 ml of concentrated hydrochloricacid is stirred at 100° for 1.5 hours. After cooling to roomtemperature, the reaction mixture is diluted with a little water,filtered and rendered alkaline by the addition of sodium hydroxidesolution. The reaction mixture is extracted with ethyl acetate, and theorganic phase is washed neutral with dilute sodium chloride solution,dried over magnesium sulphate and concentrated by evaporation. Meltingpoint 176°-178° (from ethyl acetate/petroleum ether).

Manufacture of the starting material:

(b) 3-allyl-1-(4-nitrophenyl)-3-azabicyclo[3.1.1]heptane-2,4-dione

0.36 g of sodium hydride is added to a solution of 2.46 g of1-(4-nitrophenyl)-3-azabicyclo[3.1.1]heptane-2,4-dione in 25 ml ofN,N-dimethylformamide and the whole is stirred at room temperature for30 minutes. 1.27 ml of allyl bromide dissolved in 10 ml ofN,N-dimethylformamide are then added dropwise thereto. When the reactionis complete, the reaction mixture is freed of N,N-dimethylformamide. Theresidue is partitioned between ethyl acetate and water, and the organicphase is dried over magnesium sulphate and, after concentration byevaporation and subsequent recrystallisation from ethylacetate/petroleum ether, the product is obtained having a melting pointof 146°-147°.

EXAMPLE 28 (a) 1-(4-aminophenyl)-3-propoargyl-3-azabicyclo[3.1.1]

heptane-2,4-dione

A mixture of 1.6 g of1-(4-nitrophenyl)-3-propargyl-3-azabicyclo[3.1.1]heptane-2,4-dione and4.2 g of tin powder in 12 ml of water and 12 ml of concentratedhydrochloric acid is stirred at 100° for 1 hour. After cooling to roomtemperature, the reaction mixture is diluted with a little water,filtered and rendered alkaline by the addition of sodium hydroxidesolution. The reaction mixture is extracted with ethyl acetate, and theorganic phase is washed neutral with dilute sodium chloride solution,dried over magnesium sulphate and concentrated by evaporation. Afterpurification by chromatography over silica gel in the system ethylacetate/hexane 1:1, the title compound is obtained. R_(f) (ethylacetate/hexane 1:1)=0.15.

Manufacture of the starting material:

(b) 1-(4-nitrophenyl)-3-propargyl-3-azabicyclo[3.1.1]heptane-2,4-dione

0.36 g of sodium hydride is added to a solution of 2.46 g of1-(4-nitrophenyl)-3-azabicyclo[3.1.1]heptane-2,4-dione in 25 ml ofN,N-dimethylformamide and the whole is stirred at room temperature for30 minutes. 0.97 ml of propargyl bromide dissolved in 10 ml ofN,N-dimethylformamide is then added dropwise thereto. When the reactionis complete, the reaction mixture is freed of N,N-dimethylformamide. Theresidue is partitioned between ethyl acetate and water, and the organicphase is dried over magnesium sulphate and, after concentration byevaporation and subsequent recrystallisation from ethylacetate/petroleum ether, the product is obtained having a melting pointof 166°-168°.

EXAMPLE 29 Lacquer-coated tablets

Lacquer-coated tablets containing 300 mg of1-(4-aminophenyl)-3-n-propyl-3-azabicyclo[3.1.1]heptane-2,4-dione can bemanufactured as follows:

    ______________________________________                                        Composition for 10,000 tablets                                                ______________________________________                                        1-(4-aminophenyl)-3-n-propyl-3-                                                                       3000.0  g                                             azabicyclo[3.1.1]heptane-2,4-dione                                            corn starch             680.0   g                                             colloidal silica        200.0   g                                             magnesium stearate      20.0    g                                             stearic acid            50.0    g                                             sodium carboxymethyl starch                                                                           250.0   g                                             water                   q.s.                                                  ______________________________________                                    

A mixture of1-(4-aminophenyl)-3-n-propyl-3-azabicyclo[3.1.1]heptane-2,4-dione, 50 gof corn starch and the colloidal silica is worked into a moist mass witha starch paste comprising 250 g of corn starch and 2.2 kg ofdemineralised water. This mass is forced through a sieve of 3 mesh widthand dried at 45° for 30 minutes in a fluidised bed drier. The drygranulate is pressed through a sieve of 1 mm mesh width, mixed with apreviously sieved mixture (1 mm sieve) of 330 g of corn starch, themagnesium stearate, the stearic acid and the sodium carboxymethylstarch, and compressed to form slightly domed tablets.

In a coating vessel of 45 cm diameter, the compacts are covered with asolution of 20 g of shellac and 40 g of hydroxypropylmethylcellulose(low viscosity) in 110 g of methanol and 1350 g of methylene chloride byspraying uniformly for 30 minutes; drying is effected by simultaneouslyblowing in air at 60°.

Instead of the above-mentioned active ingredient it is also possible touse the same amount of a different active ingredient according to theinvention.

We claim:
 1. A compound of the formula ##STR13## In which R₂ representshydrogen, lower alkyl, lower alkanoyl or lower alkanesulphonyl, R₃represents hydrogen or lower alkyl; R₄ represents hydrogen, lower alkyl,phenyl or phenyl substituted by --N(R₂)(R₃); and Y₁ and Y₂ represent,independently of the other, hydroxy, halogen, lower alkoxy, tri-loweralkylsilyloxy, lower alkanesulphonyloxy, benzenesulphonyloxy orp-toluenesulphonyloxy; or Y₁ and Y₂ together represent --O--; or a saltthereof.
 2. A compound according to claim 1 of the formula III, in whichR₂ and R₃ represent hydrogen; R₄ represents hydrogen, lower alkyl,phenyl or phenyl substituted by --N(R₂)(R₃); and Y₁ and Y₂ represent,independently of the other, hydroxy, halogen, lower alkoxy, tri-loweralkylsilyloxy, lower alkanesulphonyloxy, benzenesulphonyloxy orp-toluenesulphonyloxy; or Y₁ and Y₂ together represent --O--; or a saltthereof.
 3. A compound according to claim 1 of the formula III in whichR₂ and R₃ represent hydrogen, R₄ represents hydrogen or lower alkyl, andY₁ and Y₂ represent hydroxy, halogen, lower alkoxy, tri-loweralkylsilyloxy, lower alkanesulphonyloxy, benzenesulphonyloxy orp-toluenesulphonyloxy; or a salt thereof.
 4. A compound according toclaim 1 of the formula III in which R₂, R₃ and R₄ represent hydrogen andY₁ and Y₂ represent hydroxy, halogen or lower alkoxy; or a salt thereof.5. Cis-1-(4-aminophenyl)-1,3-cyclobutanedicarboxylic acid according toclaim 1.